Join us   Log in  

PHARMASPIRE - Volume 13, Issue 4 , October - December, 2021

Pages: 135-139
Print Article   Download XML  Download PDF

Role of membrane transporters in cisplatin induced nephrotoxicity

Author: Sakshi Sakshi, Gaaminepreet Singh

Category: Pharmaceutics


Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (Ctr1), the copper transporter 2 (Ctr2), the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2), and the multidrug extrusion transporter 1 (MATE1). Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also non-target cells possibly mediating specific effects and side effects of the chemotherapeutic drug. this paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters.

Keywords: Nephrotoxicity, ototoxicity, neurotoxicity, multidrug extrusion transporter 1, Organic cation transporter 2, copper transporter 2


  1. Bastiancich C, Danhier P, Préat V, Danhier F. Anticancer drug-loaded hydrogels as drug delivery systems for the local treatment of glioblastoma. J Control Release 2016;243:29-42.
  2. Odds FC, Brown AJ, Gow NA. Antifungal agents: Mechanisms of action. Trends Microbiol 2003;11:272-9.
  3. Hucke A, Ciarimboli G. The role of transporters in the toxicity of chemotherapeutic drugs: Focus on transporters for organic cations. J Clin Pharmacol 2016;56 Suppl 7:S157-72.
  4. Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, et al. Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor α in mammalian retinal pigment epithelium. J Biol Chem 2000;275:20676-84.
  5. Ciarimboli G. Membrane transporters as mediators of cisplatin side-effects. Anticancer Res 2014;34:547-50.
  6. Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 2005;4:307-20.
  7. Florea A-M, Büsselberg D. Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel) 2011;3:1351-71.
  8. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol 2014;740:364-78.
  9. Harrach S, Ciarimboli G. Role of transporters in the distribution of platinumbased drugs. Front Pharmacol 2015;6:85.
  10. Monneret C. Platinum anticancer drugs. From serendipity to rational design. In: Annales Pharmaceutiques Francaises. Amsterdam, Netherlands: Elsevier; 2011. p. 286-95.
  11. Ciarimboli G. Membrane transporters as mediators of cisplatin effects and side effects. Scientifica (Cairo) 2012;2012:473829.
  12. Abumrad N, Harmon C, Ibrahimi A. Membrane transport of long-chain fatty acids: Evidence for a facilitated process. J Lipid Res 1998;39:2309-18.
  13. Farrell NP. Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets. Chem Soc Rev 2015;44:8773-85.
  14. Mezencev R. Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: The complex world of the platinum complex. Curr Cancer Drug Targets 2014;14:794-816.
  15. Woods D, Turchi JJ. Chemotherapy induced DNA damage response: Convergence of drugs and pathways. Cancer Biol Ther 2013;14:379-89.
  16. Perazella MA, Moeckel GW. Nephrotoxicity from chemotherapeutic agents: Clinical manifestations, pathobiology, and prevention/therapy. In: Seminars in Nephrology. Amsterdam, Netherlands: Elsevier; 2010. p. 570-81.
  17. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: A review. Am J Med Sci 2007;334:115-24.
  18. Bokemeyer C, Berger CC, Hartmann JT, Kollmannsberger C, Schmoll HJ, Kuczyk MA, et al. Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. Br J Cancer 1998;77:1355.
  19. Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, et al. Organic cation transporter 2 mediates cisplatin-induced oto-and nephrotoxicity and is a target for protective interventions. Am J Pathol 2010;176:1169-80.
  20. Langer T, am Zehnhoff-Dinnesen A, Radtke S, Meitert J, Zolk O. Understanding platinum-induced ototoxicity. Trends Pharmacol Sci 2013;34:458-69.
  21. Sheth S, Mukherjea D, Rybak LP, Ramkumar V. Mechanisms of cisplatininduced ototoxicity and otoprotection. Front Cell Neurosci 2017;11:338.
  22. McLaren N. An Investigation into Normative Responses for the Upper Limb Neurodynamic Test with Radial Nerve Bias; 2013.
  23. Delforge M, Bladé J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, et al. Treatment-related peripheral neuropathy in multiple myeloma: The challenge continues. Lancet Oncol 2010;11:1086-95.
  24. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002;249:9-17.
  25. Perde-Schrepler M, Fischer-Fodor E, Virag P, Brie I, Cenariu M, Pop C, et al. The expression of copper transporters associated with the ototoxicity induced by platinum-based chemotherapeutic agents. Hear Res 2020;388:107893.
  26. Katano K, Kondo A, Safaei R, Holzer A, Samimi G, Mishima M, et al. Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper. Cancer Res 2002;62:6559-65.
  27. Skvortsov AN, Zatulovskiy EA, Puchkova LV. Structure-functional organization of eukaryotic high-affinity copper importer CTR1 determines its ability to transport copper, silver, and cisplatin. Mol Biol 2012;46:304-15.
  28. Blair BG, Larson CA, Safaei R, Howell SB. Copper transporter 2 regulates the cellular accumulation and cytotoxicity of cisplatin and carboplatin. Clin Cancer Res 2009;15:4312-21.
  29. Ahmed Z, Deyama Y, Yoshimura Y, Suzuki K. Cisplatin sensitivity of oral squamous carcinoma cells is regulated by Na+, K+-ATPase activity rather than copper-transporting P-type ATPases, ATP7A and ATP7B. Cancer Chemother Pharmacol 2009;63:643.
  30. Chen HH, Song IS, Hossain A, Choi MK, Yamane Y, Liang ZD, et al. Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by upregulation of copper transporter hCtr1. Mol Pharmacol 2008;74:697-704.
  31. Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function and regulation of human copper-transporting ATPases. Physiol Rev 2007;87:1011-46.
  32. Kalayda GV, Wagner CH, Buß I, Reedijk J, Jaehde U. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells. BMC Cancer 2008;8:175.
  33. Samimi G, Safaei R, Katano K, Holzer AK, Rochdi M, Tomioka M, et al. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res 2004;10:4661-9.
  34. Wensing KU, Ciarimboli G. Saving ears and kidneys from cisplatin. Anticancer Res 2013;33:4183-8.
  35. Hagenbuch B. Drug uptake systems in liver and kidney: A historic perspective. Clin Pharmacol Ther 2010;87:39-47.
  36. Ciarimboli G. Organic cation transporters. Xenobiotica 2008;38:936-71.
  37. Li Q, Guo D, Dong Z, Zhang W, Zhang L, Huang SM, et al. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs). Toxicol Appl Pharmacol 2013;273:100-9.
  38. Pabla N, Murphy RF, Liu K, Dong Z. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am J Physiol Physiol 2009;296:F505-11.
  39. Guo D, Yang H, Li Q, Bae HJ, Obianom O, Zeng S, et al. Selective inhibition on organic cation transporters by carvedilol protects mice from cisplatin-induced nephrotoxicity. Pharm Res 2018;35:204.
  40. Spreckelmeyer S, Orvig C, Casini A. Cellular transport mechanisms of cytotoxic metallodrugs: An overview beyond cisplatin. Molecules 2014;19:15584-610.
  41. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: Role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 2005;204:216-37.